Pituitary adenylate cyclase activating polypeptide (PACAP) is the newest member of the superfamily of metabolic, neuroendocrine and neurotransmitter peptide hormones that exert their action through the cAMP-mediated signal transduction pathway (Arimura, 1992, Regul. Peptides 37:287-303). The biologically active peptides are released from the biosynthetic precursor in two molecular forms, either as a 38-amino acid peptide (PACAP-38) and/or as a 27-amino acid peptide (PACAP-27) with an amidated carboxyl termini (Arimura, 1992, Regul. Peptides 37:287-303).
The highest concentrations of the two forms of the peptide are found in the brain and testis (reviewed in Arimura, supra). They are also expressed in peripheral tissues, such as adrenal gland, stomach and pancreas (Arimura, supra). The shorter form of the peptide, PACAP-27, shows 68% structural homology to vasoactive intestinal polypeptide (VIP). However, the distribution of PACAP and VIP in the central nervous system suggests that these structurally related peptides have distinct neurotransmitter functions (Koves et al., 1991, Neuroendocrinology 54:159-169). Biochemical and cloning experiments have demonstrated that there are receptors which recognize both PACAP and VIP peptides with similar affinities (reviewed in Harmar and Lutz, 1994, Trends in Pharm. Sci. 15:97-99), as well as a receptor that is specific for PACAP-38 and PACAP-27 (PACAP-Type 1 receptor) (Christophe, 1993, Biochim. Biophys. Acta 1154:183-199; Hashimoto et al., 1993, Neuron 11:333-342).
Despite the rapid progress in identifying the PACAP-Type 1 and the common PACAP/VIP receptors, the role of PACAPs in human physiology remain elusive. Furthermore, in view of the finding of common PACAP/VIP receptors some of the physiological functions previously attributed to the VIP will need to be reexamined. Recent studies have demonstrated diverse biological effects of PACAP-38, from a role in reproduction (McArdle, 1994, Endocrinology 135:815-817) to ability to stimulate insulin secretion (Yada et al., 1994, J. Biol. Chem. 269:1290-1293).